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Science (New York, N.Y.) Nov 2020Rotavirus causes severe diarrheal disease in children by broadly dysregulating intestinal homeostasis. However, the underlying mechanism(s) of rotavirus-induced...
Rotavirus causes severe diarrheal disease in children by broadly dysregulating intestinal homeostasis. However, the underlying mechanism(s) of rotavirus-induced dysregulation remains unclear. We found that rotavirus-infected cells produce paracrine signals that manifested as intercellular calcium waves (ICWs), observed in cell lines and human intestinal enteroids. Rotavirus ICWs were caused by the release of extracellular adenosine 5'-diphosphate (ADP) that activated P2Y1 purinergic receptors on neighboring cells. ICWs were blocked by P2Y1 antagonists or CRISPR-Cas9 knockout of the P2Y1 receptor. Blocking the ADP signal reduced rotavirus replication, inhibited rotavirus-induced serotonin release and fluid secretion, and reduced diarrhea severity in neonatal mice. Thus, rotavirus exploited paracrine purinergic signaling to generate ICWs that amplified the dysregulation of host cells and altered gastrointestinal physiology to cause diarrhea.
Topics: Adenosine Diphosphate; Animals; Calcium; Calcium Signaling; Female; HEK293 Cells; Humans; Jejunum; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Paracrine Communication; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y1; Rotavirus; Rotavirus Infections
PubMed: 33214249
DOI: 10.1126/science.abc3621 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jul 2022Because of its peculiar anatomical location, most patients with hypopharyngeal and cervical esophageal cancer are at advanced stage when they visit the hospital. At...
OBJECTIVES
Because of its peculiar anatomical location, most patients with hypopharyngeal and cervical esophageal cancer are at advanced stage when they visit the hospital. At present, the treatment for hypopharyngeal and cervical esophageal cancer is primarily surgical resection and radiotherapy. However, due to the wide range of surgical resection, it can often lead to a large range of annular defects. Therefore, the upper digestive tract reconstruction after tumor resection is very important. We use the free anterolateral thigh flap (ALT) and free jejunum (FJ) transfer to reconstruct the hypopharyngeal and cervical esophagus, and to investigate the effect of both reconstruction methods on upper gastrointestinal tract defects.
METHODS
A retrospective analysis was conducted to investigate the clinical data of 42 patients with hypopharyngeal and cervical esophageal cancer (Clinical Stage IV) from Jan. 2004 to Jan. 2016 in the Second Xiangya Hospital of Central South University. All patients underwent total laryngopharyngectomy and cervical esophageal resection. The hypopharyngeal circumferential and cervical esophageal defects were reconstructed with free ALT (=22) or FJ (=20). Four patients who underwent radiotherapy and chemotherapy before surgery did not receive radiotherapy or chemotherapy after surgery. The remaining 38 patients underwent postoperative radiotherapy and chemotherapy. All patients were followed up by telephone or outpatient review, with a follow-up deadline in Jan. 2021. We compared the differences between the 2 groups in postoperative complications, radiotherapy complications, and survival rate. The differences in individual characteristics between 2 groups were analyzed using Fisher test. The differences in postoperative and radiotherapy complications between two groups were analyzed using χ² test. The 3- and 5-year overall survival rates were calculated using Kaplan-Meier survival curve method.
RESULTS
In the ALT group, the postoperative complications mainly included anastomotic fistula, chylous fistula and subcutaneous hematoma of the donor site. The radiotherapy complication was anastomotic stenosis. However, in the FJ group, the postoperative complications mainly included chylous fistula, intestinal obstruction, and intestinal fistula. The radiotherapy complications mainly contained anastomotic fistula and tissue flap necrosis. The cases of postoperative complications in the ALT group and the FJ group were 7 and 5, respectively (=0.625), and the cases of radiotherapy complications were 3 and 4, respectively (=0.563). The 3-year overall survival rates in the ALT group and the FJ group were 52.9% and 46.7%, respectively, and the 5-year total survival rates were 35.1% and 31.9%, respectively (=0.53). The cases of anastomotic stenosis after radiotherapy in the ALT group were more than those in the FJ group (=0.097). However, the cases of jejunal necrosis and anastomotic fistula after radiotherapy in the FJ group were more than those in the ALT group (=0.066).
CONCLUSIONS
There are no significant differences in postoperative and radiotherapy complications and 3-and 5-year survival rates between the ALT group and the FJ group. The reconstruction with ALT is prone to develop anastomotic stricture. The reconstruction with FJ cannot withstand high-dose radiotherapy. The ALT and FJ are effective methods in the reconstruction of hypopharynx and cervical esophagus. The treatment protocol should be carefully chosen based on its advantages and disadvantages of these 2 methods.
Topics: Constriction, Pathologic; Esophageal Neoplasms; Fistula; Free Tissue Flaps; Humans; Hypopharynx; Jejunum; Necrosis; Postoperative Complications; Plastic Surgery Procedures; Retrospective Studies; Thigh
PubMed: 36039585
DOI: 10.11817/j.issn.1672-7347.2022.210763 -
The Journal of Physiology Apr 2023The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical...
The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live-cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli. Wnt1-, ChAT- and Calb1-GCaMP6 mice were used to record neurons from the jejunum and colon. We measured neuronal calcium response to KCl (75 mM), veratridine (10 μM), 1,1-dimethyl-4-phenylpiperazinium (DMPP; 100 μM) or luminal nutrients (Ensure®), in the presence or absence of intraluminal distension. In the jejunum and colon, distension generated by the presence of luminal content (chyme and faecal pellets, respectively) renders the underlying enteric circuit unresponsive to depolarizing stimuli. In the distal colon, high levels of distension inhibit neuronal response to KCl, while intermediate levels of distension reorganize Ca response in circumferentially propagating slow waves. Mechanosensitive channel inhibition suppresses distension-induced Ca elevations, and calcium-activated potassium channel inhibition restores neuronal response to KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a previously unknown tetrodotoxin-resistant neuronal response to luminal nutrient stimulation. Our results demonstrate that intestinal distension regulates the excitability of ENS circuits via mechanosensitive channels. Physiological levels of distension locally silence or synchronize neurons, dynamically regulating the excitability of enteric neural circuits based on the content of the intestinal lumen. KEY POINTS: How the enteric nervous system of the gastrointestinal tract responds to luminal distension remains to be fully elucidated. Here it is shown that intestinal distension modifies intracellular calcium levels in the underlying enteric neuronal network, locally and reversibly silencing neurons in the distended regions. In the distal colon, luminal distension is integrated by specific mechanosensitive channels and coordinates the dynamics of neuronal activation within the enteric network. In the jejunum, distension suppresses the neuronal calcium responses induced by luminal nutrients. Physiological levels of distension dynamically regulate the excitability of enteric neuronal circuits.
Topics: Mice; Animals; Calcium; Enteric Nervous System; Neurons; Intestine, Small; Jejunum; Colon; Myenteric Plexus
PubMed: 36752210
DOI: 10.1113/JP284171 -
Biomedicine & Pharmacotherapy =... Jun 2021Currently, several studies propose that the dominant intestinal bacteria are core flora. Besides keeping the homeostasis of the intestinal environment, the intestinal...
Currently, several studies propose that the dominant intestinal bacteria are core flora. Besides keeping the homeostasis of the intestinal environment, the intestinal microflora also plays a role in body metabolism, production of some vitamins, and control of barrier function. The study aimed to investigate the jejunum microbiota in diabetic rats as well as it's the relationship with Ceftriaxone sodium-mediated gut dysbiosis, diabetic parameters, and intestinal permeability. Thirty-two Wistar rats (Male) were enrolled and divided into four groups (A, B, C, and D; N = 8). Subsequently, T2DM was induced in C and D groups by HFD/STZ model and then gut dysbiosis in B and D groups via intragastric administration of Ceftriaxone sodium for two weeks. The food-water intake, body weight, fasting blood glucose, plasma insulin, HOMA-IR, intestinal permeability, and jejunum microbiota and it's histology were investigated. In this study, T2DM was associated with a significant decrease in the richness and diversity of jejunum microbiota, elevation in the intestinal permeability, and higher abundance of some opportunistic pathogens. Ceftriaxone sodium-induced gut dysbiosis declined food-water intake, damagedthe villi of jejunum tissue, increased intestinal permeability, and affected the diversity of jejunum microbiota. In diabetic rats, Ceftriaxone sodium-mediated gut dysbiosis also declined the abundance of someSCFAs bacteria and raised the abundant of some opportunistic bacteria such as Staphylococcus_sciuri. Interestingly, we found that several bacteria were negatively correlated with HOMA-IR, fasting blood glucose, body weight, and intestinal permeability. Overall, the study highlighted the jejunum microflora alterations in HFD/STZ diabetic rats and assessed the effect of Ceftriaxone sodium-induced gut dysbiosis on diabetic parameters, jejunum microbiota and histology, and intestinal permeability, which are of potential for further studies.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Ceftriaxone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dysbiosis; Gastrointestinal Microbiome; Intestinal Absorption; Jejunum; Male; Permeability; Rats, Wistar; Streptozocin; Rats
PubMed: 34311521
DOI: 10.1016/j.biopha.2020.111094 -
Parkinsonism & Related Disorders Apr 2022The objective of this study was to compare the pharmacokinetics (PK) of levodopa (LD) from 24-h continuous subcutaneous infusion of foslevodopa/foscarbidopa to the LD... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The objective of this study was to compare the pharmacokinetics (PK) of levodopa (LD) from 24-h continuous subcutaneous infusion of foslevodopa/foscarbidopa to the LD pharmacokinetics from 16-h levodopa-carbidopa intestinal gel (LCIG) followed by night-time oral LD/carbidopa (CD) doses.
METHODS
This was a Phase 1, open-label, randomized, 2-period crossover study conducted in 25 male and female healthy volunteers.
RESULTS
The LD exposures (C, AUC and AUC∞) following subcutaneous infusion of 700/35 mg foslevodopa/foscarbidopa over 24 h were similar (<8% difference) to those of LCIG 350/87.5 mg LD/CD administered over 16 h followed by two 100/25 mg LD/CD oral doses at 18 and 21 h after the start of LCIG delivery.
CONCLUSION
Foslevodopa/foscarbidopa subcutaneous infusion provides levodopa exposures comparable to LCIG throughout the day.
GOV IDENTIFIER
Not Applicable.
Topics: Antiparkinson Agents; Carbidopa; Cross-Over Studies; Dopamine Agonists; Drug Combinations; Female; Gels; Humans; Infusions, Subcutaneous; Jejunum; Levodopa; Male; Parkinson Disease
PubMed: 35339102
DOI: 10.1016/j.parkreldis.2022.03.012 -
Current Microbiology Mar 2023Gut microbiota contributes to human health. Plenty of studies demonstrate that antibiotics can disrupt gut ecosystem leading to dysbiosis. Little is known about the...
Gut microbiota contributes to human health. Plenty of studies demonstrate that antibiotics can disrupt gut ecosystem leading to dysbiosis. Little is known about the microbial variation of appendix and its up/downstream intestine after antibiotic treatment. This study aimed to investigate the microbiome and mucosal morphology of jejunum, appendix, and colon of rats in health and dysbiosis. A rodent model of antibiotic-induced dysbiosis was employed. Microscopy was used to observe mucosal morphological changes. 16S rRNA sequencing was performed for identifying bacterial taxa and microbiome structure. The appendices of dysbiosis were found enlarged and inflated with loose contents. Microscopy revealed the impairment of intestinal epithelial cells. High-throughput sequencing showed the Operational Taxonomic Units changed from 361 ± 33, 634 ± 18, 639 ± 19 in the normal jejunum, appendix, colon to 748 ± 98, 230 ± 11, 253 ± 16 in the disordered segments, respectively. In dysbiosis, Bacteroidetes translocated inversely from the colon and appendix (0.26%, 0.23%) to the jejunum (13.87% ± 0.11%); the relative abundance of all intestinal Enterococcaceae increased, while Lactobacillaceae decreased. Several bacterial clusters were found correlated to the normal appendix, whereas nonspecific clusters correlated to the disordered appendix. In conclusion, species richness and evenness reduced in the disordered appendix and colon; similar microbiome patterns were shared between the appendix and colon regardless of dysbiosis; site-specific bacteria were missing in the disordered appendix. Appendix is likely a transit region involving in upper and lower intestinal microflora modulation. The limitation of this study is all the data were derived from rats. We must be cautious about translating the microbiome results from rats to humans.
Topics: Humans; Rats; Animals; Dysbiosis; Jejunum; RNA, Ribosomal, 16S; Microbiota; Colon; Anti-Bacterial Agents
PubMed: 36877409
DOI: 10.1007/s00284-023-03224-0 -
Cell Reports Jul 2023A major cause of intestinal failure (IF) is intestinal epithelium necrosis and massive loss of enterocytes, especially in the jejunum, the major intestinal segment in...
A major cause of intestinal failure (IF) is intestinal epithelium necrosis and massive loss of enterocytes, especially in the jejunum, the major intestinal segment in charge of nutrient absorption. However, mechanisms underlying jejunal epithelial regeneration after extensive loss of enterocytes remain elusive. Here, we apply a genetic ablation system to induce extensive damage to jejunal enterocytes in zebrafish, mimicking the jejunal epithelium necrosis that causes IF. In response to injury, proliferation and filopodia/lamellipodia drive anterior migration of the ileal enterocytes into the injured jejunum. The migrated fabp6 ileal enterocytes transdifferentiate into fabp2 jejunal enterocytes to fulfill the regeneration, consisting of dedifferentiation to precursor status followed by redifferentiation. The dedifferentiation is activated by the IL1β-NFκB axis, whose agonist promotes regeneration. Extensive jejunal epithelial damage is repaired by the migration and transdifferentiation of ileal enterocytes, revealing an intersegmental migration mechanism of intestinal regeneration and providing potential therapeutic targets for IF caused by jejunal epithelium necrosis.
Topics: Animals; Jejunum; Enterocytes; Zebrafish; Cell Transdifferentiation; Intestinal Mucosa; Necrosis
PubMed: 37342912
DOI: 10.1016/j.celrep.2023.112660 -
Poultry Science Jan 2022The study was aimed to evaluate the morphology and immune function development of the jejunum and ileum in squab pigeons (Columba livia), by determining the villus...
The study was aimed to evaluate the morphology and immune function development of the jejunum and ileum in squab pigeons (Columba livia), by determining the villus ultrastructure, secretory IgA, and cytokines. Eight squabs were randomly selected and sampled on the day of hatch (DOH), d 7 (D 7), 14 (D 14), and 21 (D 21) post-hatch, respectively. The results showed that under transmission electron microscope, the enterocyte circumference in jejunum and ileum decreased with age. The tight junction involved in enterocyte circumference of jejunal villi plateaued from D 7, whereas that of ileal villi changed irregularly. The microvilli of jejunal and ileal villi was maximum at D 14. Under scanning electron microscope, the villus morphology of jejunum and ileum appeared finger-shaped at DOH. After D 7, the jejunal villi were still finger-shaped whereas the ileal villi were leaflike. The secretory IgA in jejunum was significantly increased at D 21. The TGF-β decreased linearly in jejunum and ileum. The anti-inflammatory cytokines increased linearly and proinflammatory cytokines decreased linearly in jejunum and ileum with age. In conclusion, the morphological changes of jejunal epithelium were concentrated at DOH-D 7 and ileal epithelium at DOH-D 14 mainly. The changes in mucus layer and immune-related factors of jejunum and ileum persisted for almost the entire period.
Topics: Animals; Chickens; Columbidae; Ileum; Immunity; Jejunum
PubMed: 34784512
DOI: 10.1016/j.psj.2021.101529 -
The Journal of Nutrition Nov 2022In vivo data on intestinal fat absorption in weanling piglets are scarce.
BACKGROUND
In vivo data on intestinal fat absorption in weanling piglets are scarce.
OBJECTIVES
This study aimed to investigate the effect of weaning stress on intestinal fat absorption.
METHODS
Eighteen 7-d-old sow-reared piglets (Duroc-Landrace-Yorkshire) were assigned to 3 groups (n = 6/group, 3 males and 3 females per group). Piglets were nursed by sows until 24 d of age (suckling piglets, S), or weaned at 21 d of age to a corn-soybean meal-based diet until 24 d (3 d postweaning, W3) or 28 d (7 d postweaning, W7) of age, respectively. Duodenum, jejunum, and ileum were collected to determine intestinal morphology and abundance of proteins related to fat absorption.
RESULTS
Compared with the S group, the W3 group had lower villus height (17-34%) and villus height to crypt depth ratio (13-53%), as well as 1-1.45 times greater crypt depth; these values were 1.18-1.31, 0.69-1.15, and 1.47-1.87 times greater in the W7 group than in the W3 group, respectively. Compared with the S group, weaning stress for both W3 and W7 groups reduced intestinal alkaline phosphatase activity (26-73%), serum lipids (26-54%), and abundances of proteins related to fatty acid transport [fatty acid transport protein 4 (FATP4) and intestinal fatty acid-binding protein (I-FABP)] and chylomicron assembly [microsomal triglyceride transfer protein (MTTP), apolipoprotein A-IV (APOA4), B (APOB), and A-I (APOA1)] in the duodenum and ileum (10-55%), as well as in the jejunum (25-85%). All these indexes did not differ between W3 and W7 groups. Compared with the S group, the W3 group had lower mRNA abundances of duodenal APOA4 and APOA1 (25-50%), as well as jejunal FATP4, IFABP, MTTP, APOA4, and APOA1 (35-50%); these values were 5-15% and 10-37% lower in the W7 group than in the W3 group, respectively.
CONCLUSIONS
Weaning stress in piglets attenuates the expression of intestinal proteins related to fatty acid transport (FATP4 and I-FABP) and chylomicron synthesis (APOA4).
Topics: Male; Swine; Animals; Female; Weaning; Intestines; Jejunum; Intestinal Mucosa; Intestinal Absorption; Fatty Acids; Dietary Supplements
PubMed: 36774105
DOI: 10.1093/jn/nxac177 -
Toxins Jan 2022Fumonisin B1 (FB1) is a widespread mycotoxin produced by fungal species-mainly in maize, one of the plants most commonly used for food and feed. Pigs and horses are the...
Fumonisin B1 (FB1) is a widespread mycotoxin produced by fungal species-mainly in maize, one of the plants most commonly used for food and feed. Pigs and horses are the animal species most susceptible to this mycotoxin. FB1 exposure can cause highly diverse clinical symptoms, including hepatotoxicity, immunotoxicity, and intestinal barrier function disturbance. Inhibition of ceramide synthetase is a well-understood ubiquitous molecular mechanism of FB1 toxicity, but other more tissue-specific effects remain to be elucidated. To investigate the effects of FB1 in different exposed tissues, we cross-analyzed the transcriptomes of fours organs: liver, jejunum, jejunal Peyer's patches, and spleen. During a four-week study period, pigs were fed a control diet or a FB1-contaminated diet (10 mg/kg feed). In response to oral FB1 exposure, we observed common biological processes in the four organs, including predominant and recurrent processes (extracellular matrix organization, integrin activation, granulocyte chemotaxis, neutrophil migration, and lipid and sterol homeostasis), as well as more tissue-specific processes that appeared to be related to lipid outcomes (cell cycle regulation in jejunum, and gluconeogenesis in liver).
Topics: Administration, Oral; Animals; Fumonisins; Gene Expression Regulation; Genome-Wide Association Study; Jejunum; Liver; Peyer's Patches; Swine; Swine Diseases
PubMed: 35202111
DOI: 10.3390/toxins14020083